Evolution of Movement Disorders in Patients With CLN2-Batten Disease Treated With Enzyme Replacement Therapy

Objectives Neuronal ceroid lipofuscinosis type 2 (CLN2-disease) is an inherited childhood-onset neurodegenerative condition, with classical early features of speech delay, epilepsy, myoclonus, ataxia, and motor regression. This study aimed to better characterize the spectrum of movement disorders in CLN2-disease in a cohort of children receiving enzyme replacement therapy (ERT). Methods A cohort of 18 children attending a single center for treatment with cerliponase alfa ERT was systematically assessed using a standardized structured history and a double-scored, video-recorded examination using the Unified Batten Disease Rating Scale (UBDRS) and Abnormal Involuntary Movement Scale. Results Noncanonical movement disorders are common: while ataxia (89%) and myoclonus (83%) were near-universal, spasticity and dystonia were experienced by over half (61% each), with children having a median of 4 distinct movement disorder phenotypes. This progression was stereotyped with initial ataxia/myoclonus, then hyperkinesia/spasticity, and later hypokinesia. ERT slows progression of movement disorders, as measured by the UBDRS physical subscale, with 1.45 points-per-month progression before diagnosis and 0.44 points-per-month while on treatment (p = 0.019). Discussion Movement disorders are a core feature of CLN2-disease and follow a typical pattern of progression which is slowed by ERT. Identifying and treating movement disorders should become standard, especially given increased patient survival.


Introduction
Neuronal ceroid lipofuscinoses (NCL) are a group of inherited lysosomal disorders that typically cause progressive neurodegeneration in childhood, with the unifying feature of accumulation of autoflourescent ceroid lipofuscin.3][4] Cerliponase alfa (Brineura, BioMarin) is an enzyme replacement therapy (ERT) delivered by fortnightly intracerebroventricular infusion that prolongs life and slows progression in classical CLN2-disease. 5N2-disease natural history has been characterized using functional scales, typically either Hamburg (modified to CLN2-Disease Rating Scale) or Weill-Cornell, which focus on seizures, ambulation, language, and visual function.2,4,6 Some movement disorders are well-recognized: ataxia is an early hallmark contributing to loss of ambulation; myoclonus is almost universal representing both epileptic and nonepileptic movements.2 Other movement disorders such as chorea, tremor, and dystonia are less well characterized.
In this study, we aimed to systematically characterize the range of movement disorders in children with CLN2-disease using cross-sectional standardized clinical assessment and structured data review of a cohort of children receiving ERT at a single center.

Standard Protocol Approvals, Registrations, and Patient Consents
Children with biallelic pathogenic TPP1 variants and confirmed CLN2-disease attending Great Ormond Street Hospital for regular administration of ERT were recruited.This study was approved by the United Kingdom Research Ethics Service (Research Ethics Committee: London-Bloomsbury: 13/LO/0168).Families provided written consent for inclusion and video recording.9][10] Statistical Analysis Summary statistics on clinical data were included for 18 children and UBDRS physical subscale (UBDRSp) and AIMS scores for 15 children.Statistical analysis used R (version 4.3.2). 11 Time-to-event analysis was performed on Kaplan-Meier cumulative incidence curves for each movement phenotype using the survminer package 12 ; significance was tested with log-rank tests and Holm correction where multiple comparisons were made.UBDRSp score correlation with age was assessed using the nonparametric Spearman rank; the contribution to this correlation from age at diagnosis, time to ERT start, and time on ERT was assessed using multiple regression in R (see eMethods for full detail).

Data Availability
All anonymous data have been shared in the eMethods; further patient-level data sharing may be possible by request to the corresponding author subject to legal and ethical considerations.

Movement Disorders Progress in a Typical Pattern
Children with CLN2-disease follow a typical pattern of progression of their movement disorder.Figure 1A shows a time-to-event analysis with cumulative probability of developing the most common phenotypes: median age at ataxia onset is 4 years, myoclonus 5 years, spasticity 7.5 years, dystonia 8 years, and hypokinesia 10 years (log-rank test of differences p = 0.0014).Figure 1B shows phenotype progression in relation to ages at diagnosis and ERT commencement for each individual.

ERT Slows Worsening of UBDRS Score and Movement Disorder Progression
UBDRSp scores, which comprises function and movement disorder severity, increase with age at assessment (r = 0.63, p = 0.012).Multiple regression analysis showed a greater contribution from age at diagnosis (1.45 UBDRSp-points-per-month before diagnosis, p = 0.003) compared with while receiving ERT (0.44 UBDRSp-points-per-month on ERT, p = 0.019) (eMethods).This indicates that progression slows but does not stop after starting ERT.There was no apparent correlation with other variables such as sex or common genotype.

Treatment for Movement Disorders Is Variable
Only half of the cohort had received medications or treatments for movement disorders, despite 9 of 15 having at least one moderate/severe movement disorder noted on examination.On average, 2 medications had been trialed per patient (range 0-4); gabapentin and clonazepam were most commonly used (5 and 4 patients, respectively) (Table 1).Parents reported that gabapentin was generally effective for dystonia [mean dose 43 mg/kg/d, range 26-60 mg/kg/d], but less consistent benefit was reported for other medications.Medication-related worsening of symptoms was not reported,  and side effects were rarely reported (drowsiness with gabapentin, n = 2; reduction in central tone with baclofen, n = 1).

Discussion
This cross-sectional assessment of movement disorders in a cohort of children with CLN2-disease receiving ERT shows that movement disorders are near-universal, follow a typical pattern of development, and that ERT appears to slow progression.This systematic analysis corroborates and expands on previously described frequent pyramidal signs and infrequent chorea, tremor, and dystonia in ERT-naive children. 2 It is likely that these movement disorders are part of the natural history of CLN2-disease, rather than a consequence of treatment, and predominantly reflect disease progression before starting ERT.Even when ERT is started, it can take several months to see improvement in CLN2 scores and biomarkers. 13It is also possible that ERT is prolonging lifespan, which may alter the natural history of disease, resulting in a new "ERT-treated disease phenotype" including a spectrum of movement disorders.Although intracerebroventricular delivery of recombinant TPP1 in dogs led to widespread CNS penetration including key areas for motor control, 14 future data on the biodistribution of ERT in patients will be informative for understanding which regions of the brain are effectively targeted.
The progression of movement symptoms from ataxia and myoclonus (median age 4-5 years) through to both pyramidal (spasticity) and extra-pyramidal (dystonia) features (age 8 years) and then to hypokinesia (age 10 years), indicates progressive functional impairment.Early myoclonus may be cortical or subcortical in origin, 3,4 but often accompanies the onset of generalized convulsive seizures.Loss of ambulation may initially be related to ataxia but also negative myoclonus and later spasticity and dystonia.This stereotyped progression bears some similarity to other NCLs and neurometabolic disorders such as juvenile Tay-Sachs disease. 15Whether the observed hypokinesia is parkinsonian remains to be determined, as other features such as bradykinesia and rigidity are not seen.
Qualitative assessment (Figure 1B) supported by multiple regression analysis indicates slower progression on ERT, suggesting that progression of movement disorders slows with treatment, in keeping with the slower overall disease progression on ERT.
Notably, 3 patients (03, 09, 13) presented atypically with a movement disorder other than myoclonus or ataxia before epilepsy: 2 with dystonia and another with tremor.Two (03, 14) have a predominantly hyperkinetic phenotype, with marked choreiform and ballistic movements that are treatmentrefractory.With increasing availability of genomic testing, enzyme assay, and ERT, CLN2-disease should be considered early in the diagnostic pathway for children with movement disorders.
This study is limited in assessment of natural history, as all participants started ERT at varying disease stages as it became available.Given that ERT slows disease progression, it is likely that this study underestimates the burden of movement disorders in untreated disease.In addition, our ERT access program excluded children with very severe disease, which might have led to study bias by negative selection.
In conclusion, this study provides an in-depth assessment of movement disorders associated with CLN2-disease in a cohort of children receiving ERT.While ataxia and myoclonus have long been hallmarks of early CLN2-disease, other movement disorder phenotypes have received less focus.In this era of disease-modifying treatment and increased survival, a more holistic approach to management and treatment can be informed by this assessment of phenotype progression that will better maintain quality of life, inclusion, and functional attainment.

Figure
Figure Movement Disorder Presentation and Phenotypes

Table
Summary of Clinical Details and Movement Disorders Present or Previously Reported